Mutagenicity of carcinogenic heterocyclic amines in Salmonella typhimurium YG strains and transgenic rodents including gpt delta

Nohmi, Takehiko; Watanabe, Masahiko

doi:10.1186/s41021-021-00207-0

Table 3 In vivo mutagenicity of heterocyclic amines in transgenic mice and rats

From: Mutagenicity of carcinogenic heterocyclic amines in Salmonella typhimurium YG strains and transgenic rodents including gpt delta

Chemical	Species	Gender	Administration	Selection	Organ	Dose	Judgement	Remarks	Reference
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	Muta Mouse, i.e., (BALB/c x DBA/2)CD2 F1 mice, but was heterozygous at the endogenous Dlb-1 locus.	male and female	Diet for 30, 60 and 90 days and sacrificed between 1 and 3 weeks after the last treatments. Diet for 30 days at a dose of 250 ppm.	lacI	small intestine	100 ppm	+	Accumulation of mutations at both loci (lacI and Dlb-1) appears to be linear with both PhIP concentration and duration of exposure. PhIP was more mutagenic in the small intestine than in the colon.	[112]
						250 ppm	+
						400 ppm	+
					colon	100 ppm	+
						250 ppm	±
						400 ppm	+
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	Muta Mouse = (BALB/c x DBA/2)CD2 F1 mice	male	Gavage for 4 days, and sacrificed 7 days later.	lacZ	large intestine	20 mg/kg/day	+	No mutagenicity was observed in any organs examined at doses of 2 and 0.2 mg/kg/day.	[113]
	Muta Mouse = (BALB/c x DBA/2)CD2 F1 mice		Gavage for 4 days, and sacrificed 7 days later.		small intestine	20 mg/kg/day	+
					liver	20 mg/kg/day	+
					kidney	20 mg/kg/day	–
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	Muta Mouse	male	per os for 4 days and sacrified 7 days after the last treatment.	lacZ	intestine	20 mg/kg/day	+	About 2/3 (65%) of the induced mutations were base substitutions and about half were G:C to T:A transversions. DNA was obtained from Lynch et al. [113].	[114]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	male and female	diet for 60 days	lacI	colon	400 ppm	+	G:C deletions including deletions at 5′-GGGA-3′ were the most frequent mutations. No significant difference was observed in MF between male and female.	[109]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	(C57BL/6 x SWR)F1 mice	male and female	diet for 60 days	lacI	colon	400 ppm	+	G:C to T:A transversions in runs of guanine were the hot spot of base substitutions. DNA was obtained from Zhang et al. [112].	[115]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	C57 BL6/J mice	male	diet for 13 weeks	gpt and Spi⁻	colon	400 ppm	+	The highest MF was observed in the colon followed by the spleen and the liver in both gpt and Spi⁻ selections. There were no gender differences in MF in the colon and the liver.	[110]
					spleen		+
					liver		+
					testis		–
					brain		–
					bone marrow		–
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	(BBR x SD)F1 rats	female	gavage for 2 weeks (5 consequtive days per week)	lacI	Mammary duct	65 mg/kg/day	+	G:C to T:A transversions were the most frequent mutations, followed by G:C deletions including deletions at GGGA sequence.	[116]
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)	C57 BL6/J mice	male	diet for 13 weeks	gpt and Spi⁻	colon	400 ppm	+	G:C to T:A transversions and single G:C deletions were the most frequently observed mutations by gpt and Spi⁻ selections, respectively. DNA was obtained from Masumura et al. [110].	[117]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	male and female	diet for 60 days	cII	colon	400 ppm	+	Mutation spectra were similar between cII and lacI assays. G:C to T:A transversions were the most frequent mutations followed by G:C to C:G transversions, G:C to A:T transitions and G:C deletions.	[118]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	male	diet for 61 days	lacI	prostate	200 ppm	+	The predominant mutation was G:C to T:A transversions and G:C deletions.	[119]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	male and female	diet for 61 days	lacI	cecum	200 ppm	+	MF in the colon was higher than that in the cecum. G:C to T:A transversions were the most frequent mutations, followed by G:C to C:G transversions and G:C deletions. No differences in MF were observed between male and female in the colon although tumors were induced in the colon of male rats. Hormone may play a role in the induction of tumors in the colon of male rats.	[111]
					proximal colon	200 ppm	+
					distal colon	200 ppm	+
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	male	diet for 61 days	lacI	distal colon	200 ppm	+	The rats were fed a diet with conjugated linoleic acid (CLA, 0.5%, wt/wt) or 1,2-dithiole-3-thione (DTT, 0.005%, wt/wt) starting one week before PhIP treatments of 61 days. CLA and DTT significantly reduced PhIP-induced MF in the distal colon. In contrast, DTT significantly elevated MF in the cecum.	[120]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)					cecum	200 ppm	+		[120]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	male and female	diet for 47 days	lacI	distal colon	100 ppm	+	The rats were fed a diet with conjugated linoleic acid (CLA, 1%, wt/wt) one week before starting PhIP treatments of 47 days. CLA reduced the MF in the distal colon but not in the cecum.	[121]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)					cecum	100 ppm	+
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	male and female	diet for 47 days	lacI	kidney	100 ppm	+	MF in male was significantly higher than that in female. Conjugated linoleic acid inhibited the mutation in female but not in male.	[122]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	female	oral dosing for 12 days	lacI	mammary gland	75 mg/kg	+	Young (43-day-old) and aged (150-day-old) female rats exhibited similar PhIP-induced MFs in the mammary gland.	[123]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	male and female	intraperitoneal injection	lacI	colon	100 mg/kg	+	Calory restriction with a 40%-reduced diet for 22 weeks did not affect PhIP-induced MF in the colon.	[124]
2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)	F344 rats	male	gavage for three times a week for 4 weeks or 8 weeks	cII	liver	70 mg/kg	–	MFs were significantly elevated by PhIP treatments in the colon, the spleen, the seminal vesicles and all lobes of the prostate. The MFs were higher in 8-week treatments than in 4-week treatments.	[125]
			gavage for three times a week for 4 weeks or 8 weeks		kidney		–
					ventral prostate		+
					dorsolateral prostate		+
					anterior prostate		+
					seminal vesicle		+
					colon		+
					spleen		+
2-amino-3-methylimidazo[4,5-f]quinoline (IQ)	C57Bl/lacZ (=C57Bl x Muta Mouse) and c-myc/lacZ (=C57Bl/6 J x CBA/J x Muta Mouse)	?	p.o. for 10 days and sacrificed 4 weeks after the dosing	lacZ	liver	20 mg/kg/day	+	c-myc appears to enhance IQ-induced MF in the liver.	[126]
2-amino-3-methylimidazo[4,5-f]quinoline (IQ)	F344 rats	male	gavate for a single day or for 5 consecutive days	lacI	liver	20 mg/kg/day	+	MF was highest in the liver, followed by the colon and the kidney. GC transversions in the liver and the colon and 1 bp G:C deletions in the liver and the kidney were induced. A single G deletion in the sequence 5′-CGGG was detected in the liver and the colon. Preferential sequences for base substitutions and deletions were 5′-CGC/T-3′ and 5′-CGGA-3′, respectively.	[127]
			gavate for a single day or for 5 consecutive days		colon	20 mg/kg/day	+
					kineny	20 mg/kg/day	+
2-amino-3-methylimidazo[4,5-f]quinoline (IQ)	F344 rats	male	diet for 3 weeks	cII	liver	20 mg/kg/day	–	IQ induced higher MF in the liver than in the colon.	[128]
						70 mg/kg/day	+
						200 mg/kg/day	+
					colon	20 mg/kg/day	–
						70 mg/kg/day	+
						200 mg/kg/day	+
2-amino-3-methylimidazo[4,5-f]quinoline (IQ)	F344 rats	male	diet for 3 weeks	lacI	colon	70 ppm	+	The rats were fed a diet with IQ or IQ + sucrose (0, 3.45% or 13.4%) for 3 weeks. IQ and sucrose increased MF independently in the colon. There were no interactions between IQ and sucrose interms of induction of mutations.	[129]
2-amino-3-methylimidazo[4,5-f]quinoline (IQ)	S.D. rats	female	diet for 13 weeks	gpt	liver	300 ppm	+	G:C to T:A transversions and single guanine deletions were induced by IQ.	[130]
2-amino-3-methylimidazo[4,5-f]quinoline (IQ)	F344 rats	male	diet for 4 weeks	gpt and Spi⁻	liver	0.1 ppm	–	Spi⁻ selection and GST-P positive foci assay were positive only in 100 ppm, while gpt assay was positive in 10 and 100 ppm. Frequencies of G:C to T:A transversions in the gpt gene were significantly increased in 1, 10 and 100 ppm in a dose-dependent manner.	[131]
						1 ppm	–
						10 ppm	+
						100 ppm	+
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ)	C57BL/6 mice	female	diet for 12 weeks	lacI	liver	300 ppm	+	G:C to T:A transversions, followed by G:C to A:T transitions, were induced in the liver and the bone marrow. DNA was obrained from Suzuki et al. [132].	[133]
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ)					bone marrow	300 ppm	+		[133]
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ)	C57BL/6 mice	female	diet for 1, 4, 12 weeks	lacI	bone marrow	300 ppm	+	MF was in the order of the colon, the bone marrow, the liver and the forestomach. The MF increased in a feeding period-dependent manner. No mutagenicity was observed in the heart.	[132]
					liver	300 ppm	+
					forestomatch	300 ppm	+
					colon	300 ppm	+
					heart	300 ppm	–
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ)	C57BL/6 mice	female	diet for 84 days	lacI	colon	300 ppm	+	G:C to T:A transversions at 5′-GC-3′ were the hot spot of base substitutions. DNA was obtained from Suzuki et al. [132].	[115]
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)	C57Bl/lacZ (=C57Bl x Muta Mouse) and c-myc/lacZ (=C57Bl/6 J x CBA/J x Muta Mouse)	?	p.o. for 10 days, and sacrified 4 weeks after the dosing	lacZ	liver	20 mg/kg/day	+	c-myc appears to enhance MeIQx-induced MF in the liver.	[126]
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)	C57Bl/lacZ (=C57Bl x Muta Mouse) and c-myc/lacZ (=C57Bl/6 J x CBA/J x Muta Mouse)	male and female	diet for 30 or 40 weeks	lacZ	liver	600 ppm	+	MFs in the mice fed diets containing MeIQx for 30 or 40 weeks were about 40 times higher than those of untreated mice. MF in male was higher than that in female. There was a synergistic effects of MeIQx and c-myc for hepatocarcinogenesis. c-myc also enhanced MeIQx-induced MF.	[134]
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)	C57BL/6 mice	male	single intragastric administration	lacI	liver	100 mg/kg	–	No mutagenicity was observed by single intragastric administration. Mutagenicity was observed only in female by 4 weeks administration. Both sexes were positive in 12 weeks administration. MF was higher in female than in male mice, which is consistent with the sensitivity to carcinogenicity of MeIQx.	[135]
			single intragastric administration		colon	100 mg/kg	–
		male and female	diet for 4 weeks	lacI	liver	300 ppm	+ female/− male
					colon	300 ppm	+ female/− male
			diet for 12 weeks	lacI	liver	300 ppm	+
					colon	300 ppm	+
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)	C57 BL6/J mice	male	diet for 12 weeks	gpt	liver	3 ppm	–	The Liver was more sensitive to the mutagenicity of MeIQx than the colon. MF at 300 ppm for 78 weeks in liver was higher than that at the same dose for 12 weeks. Whole gpt MF and the frequencies of G:C to T:A were not significantly increased at 3 ppm.	[136]
						30 ppm	+
						300 ppm	+
			diet for 12 weeks	gpt	colon	3 ppm	–
						30 ppm	–
						300 ppm	+
			diet for 78 weeks	gpt	liver	300 ppm	+
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)	F344 rats	male	diet for 16 weeks	lacI	liver	0.01 ppm	–	MF was increased at 10 and 100 ppm. GST-P positive foci were induced at 100 ppm only. Most frequently induced mutations were frameshifts in guanine bases, followed by G to T transversions.	[137]
						0.1 ppm	–
						1 ppm	–
						10 ppm	+
						100 ppm	+
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)	B6C3F(1) p53 (+/+) or p53 (+/−) mice	female	diet for 13 weeks with or without CCl₄ (i.p. 1 ml/kg once a week)	gpt and Spi⁻	liver	300 ppm	+	G:C to T:A transversions were induced by MeIQx. CCl₄ treatments enhanced MF even in the p53-deficient background.	[138]
9-(4′-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH)	C57 BL6/J mice	male	diet for 12 weeks	gpt and Spi⁻	liver	10 ppm	+	G:C to T:A transversions, followed by G:C to A:T transitions, were the most frequent mutations detected by gpt assay. Single G deletions in run sequences were detected by Spi⁻ selection. The liver was more sensitive than the colon in terms of induction of mutations.	[139]
						20 ppm	+
				gpt	colon	10 ppm	+
						20 ppm	+
5-amino-6-hydroxy-8H-benzo [6, 7]azepino[5,4,3-de]quinolin-7-one (ABAQ)	C57 BL6/J mice	male	gavege for 3 weeks (5 consequtive days per week)	gpt and Spi⁻	liver	25 mg/kg	+	G:C to A:T transitions and A:T to C:G transversions were increased in the liver. Both gpt and Spi⁻ assays were positive in the liver but negative in the kidney.	[140]
						50 mg/kg	+
					kidney	25 mg/kg	–
						50 mg/kg	–
2-amino-9H-pyrido[2,3-b]indole (AαC)	C57Bl/lacZ (=C57Bl x Muta Mouse) and c-myc/lacZ (=C57Bl/6 J x CBA/J x Muta Mouse)	?	p.o. for 10 days, and sacrified 4 weeks after the dosing	lacZ	liver	20 mg/kg/day	+	c-myc appears to enhance MF. MF of AαC was lower than those of IQ and MeIQx although DNA adduct levels were higher in AαC than in IQ or MeIQx.	[126]
2-amino-9H-pyrido[2,3-b]indole (AαC)	Muta Mouse, i.e., (BALB/c x DBA/2)CD2 F1 mice, but was heterozygous at the endogenous Dlb-1 locus.	male and female	diet for 30 and 45 days	lacI	small intestine	800 ppm	–	AαC was mutagenic in the colon but not in the small intestine.	[112]
2-amino-9H-pyrido[2,3-b]indole (AαC)					colon	800 ppm	+		[112]
2-amino-9H-pyrido[2,3-b]indole (AαC)	(C57BL/6 x SWR) F1 mice	male and female	diet for 45 days	lacI	colon	800 ppm	+	G:C to T:A transversions at 5′-CGT-3′ was the hot spot of base substitutions. DNA was obtained from Zhang et al. [112].	[115]

Back to article page

ISSN: 1880-7062

Contact us

Submission enquiries: Access here and click Contact Us
General enquiries: info@biomedcentral.com

Genes and Environment

Contact us